Mechanisms of cellular injury and transformation

肝脏研究中心的研究人员参与了肝脏和神经系统疾病中细胞损伤和转化的分子机制的研究。有五个“迷你项目”由初级教师进行，每个具体目标定义一个研究项目由一个独立的调查员进行。具体目标#1涉及Ji Su Li，M.D.在转基因小鼠中产生/表征禽B型肝炎病毒受体，博士她最近发现p170是一种主要的肝细胞受体，并计划建立一个小动物模型来研究病毒复制。这种转基因小鼠模型将用于了解宿主对嗜肝DNA病毒感染的免疫反应，并有助于抗病毒治疗的发展。具体目标#2，由Shuping Tong，M.D.提交，博士将精确定义p170上介导病毒结合和细胞进入的氨基酸序列。他计划通过盒式交换、缺失分析和定点突变来绘制病毒结合位点。这项研究将允许寻找阻止病毒进入细胞的抗病毒剂，并有助于定义嗜肝DNA病毒生命周期的早期事件。具体目标#3将在独特的转基因小鼠模型中研究继发性细胞事件（如基因突变）在人胰岛素受体底物-1基因（IRS-1）过表达产生的非转化但持续的肝增殖刺激背景下肝细胞癌（HCC）发展中的作用。这些研究应该提供新的信息，在体内肝癌发生的多步骤过程中，以及评估生长因子的信号转导通路的相互作用，和肿瘤抑制基因的功能。具体目标#4将分析转录因子肌细胞增强因子2（MEF 2）在肝星状细胞活化中的作用，及其在调节纤维化中的潜在作用，M.P.H.这项拟议的研究将解决以下问题：1）MEF 2蛋白或活性在星状细胞活化过程中受到调节吗？2)MEF 2功能是星状细胞激活所必需的吗？以及3）在星状细胞活化过程中，哪些信号转导通路对介导MEF 2活性是重要的？具体目标#5将产生AD 7 C-NTP过表达的转基因小鼠模型，以研究体内AD神经变性的机制，Suzanne de la Monte，M.D.，M.P.H.体外神经元细胞中AD 7 C-NTP的过表达产生增加的细胞凋亡和神经炎过程的生长（异常神经炎出芽）。本项目将尝试建立一种神经退行性变的转基因小鼠模型，以确定在转基因小鼠脑中由神经元特异性表达AD 7 C-NTP诱导的表型。

Investigators at the Liver Research Center are involved in studies on the molecular mechanisms of cellular injury and transformation in liver and neurologic disease. There are five "mini-projects" conducted by junior faculty, and each Specific Aim defines a research project conducted by an independent investigator. Specific Aim #1 involves the generation/characterization of the avian hepatitis B viral receptor in transgenic mice by Ji Su Li, M.D., Ph.D. She recently identified p170 as a major hepatocyte receptor, and plans to create a small animal model to study viral replication. This transgenic mouse model will be used to understand the host immune response to hepadnaviral infection, and aid in the development of antiviral therapy. Specific Aim #2, submitted by Shuping Tong, M.D., Ph.D. will precisely define the amino acid sequence(s) on p170 that mediate viral binding and cellular entry. He plans to map the viral binding site by cassette exchange, deletion analysis, and site-directed mutagenesis. This study will permit a search for antiviral agents that block viral entry into the cell, and aid in the definition of the largely unknown early events of the hepadnaviral life cycle. Specific Aim #3 will study the role of secondary cellular events such as genetic mutation(s) in the development of hepatocellular carcinoma (HCC) in the setting of a non-transforming, but continuous, hepatic proliferative stimulus generated by over-expression of the human insulin receptor substrate-1 gene (IRS-1) in a unique transgenic mouse model. These studies should provide new information on the multi-step process of hepatocarcinogenesis in vivo, as well as to assess the interactions of a growth factor signal transduction pathway, and tumor suppressor gene function. Specific Aim #4 will analyze the role of transcription factor myocyte enhance factor 2 (MEF2) in hepatic stellate cell activation, and its potential role in regulating fibrogenesis by Zixu Mao, M.D., m.p.h. This proposed research will address the following issues: 1) are MEF2 proteins or activity regulated during stellate cell activation? 2) is MEF2 function required for stellate cell activation? And 3) which signal transduction pathways are important for mediating MEF2 activity during stellate activation? Specific Aim #5 will generate a transgenic mouse model of AD7C-NTP over-expression to study the mechanisms of AD neurodegeneration in vivo by Suzanne de la Monte, M.D., M.P.H. Over- expression of AD7C-NTP in neuronal cells in vitro produces increased apoptosis and growth of neuritic process' (aberrant neuritic sprouting). This project will attempt to establish a transgenic mouse model of neural degeneration defining the phenotype induced by neuronal specific expression of AD7C-NTP in the transgenic mouse brain.